Multi-ancestry genome- and transcriptome-wide association studies expand the susceptibility landscape for breast cancer overall and across subtypes

Breast cancer genomic studies have been conducted primarily in European-ancestry populations, limiting both diversity and statistical power. In this study, we substantially increased the representation of African- and Asian-ancestry women and markedly expanded the sample size of European descendants, creating the largest multi-ancestry dataset for breast cancer genome-wide association studies (GWAS) to date. With 237,817 cases and 1,679,059 controls, we conducted GWAS and transcriptome-wide association studies (TWAS) across ancestries and identified 326 risk loci and 113 genes associated with overall breast cancer risk at a P < 5 × 10⁻⁸ (for GWAS) and Bonferroni-corrected P of 1.54 × 10⁻⁴ (for TWAS), respectively. Of them, 153 risk loci and 69 genes were not reported previously. Subtype-specific analyses for estrogen receptor (ER) positive, ER-negative and triple-negative breast cancer (TNBC) revealed an additional 89 loci and 64 genes associated with breast cancer risk, including 61 loci and 12 genes not previously reported. Moreover, associations for 25 loci and 11 genes differed significantly by ER status, and 22 loci and eight genes were exclusively associated with risk of triple-negative breast cancer. Risk genes identified in this study were significantly enriched in pathways related to transcriptional regulation, estrogen response, mitotic spindle processes, and DNA damage repair. Together, these findings substantially expand the landscape of breast cancer susceptibility, subtype-specific genetic architecture, and provide added insights into breast cancer biology and genetics.